ABSTRACT Sudden Cardiac Death (SCD) caused by ventricular tachycardias and fibrillation (VT/VF) is a major world-wide health problem, claiming the lives of some 300,000 Americans each year. Current antiarrhythmic drug (AAD) therapy to control VT/VF is largely empirical and poorly efficacious with considerable risk of proarrhythmic effects. There remains considerable unmet need for new, safe and effective AADs that specifically target the electrophysiological underpinnings of VT/VF without compromising cardiac function. Our goal is to discover and develop a small molecule antiarrhythmic drug that will address this need. Members of the Cardiovascular Research Laboratory (CVRL) at UCLA, Drs. Hrayr Karagueuzian and Riccardo Olcese, have recently advanced our understanding of the functional regulation of the voltage dependent calcium channel CaV1.2 by the ?2?-1 subunit, and how modulation of CaV1.2 gating can reduce VT/VF triggered by early afterdepolarizations (EADs). They have also demonstrated the effect of gabapentinoids as CaV1.2 channel gating modifiers, and with this uncovered their potential therapeutic application as AADs. However, while efficacious, gabapentinoids also produce undesirable centrally mediated side effects that must be avoided in a well-tolerated chronically dosed AAD. This goal can be achieved through the design of peripherally restricted ?2?-1 ligands, i.e., compounds that are orally bioavailable but not centrally penetrant, which we aim to discover. Under Phase I SBIR funding and through use of our computational drug discovery platform, we identified two novel lead compounds that 1) bind to the ?2? subunit of the CaV1.2 channel complex with high affinity; 2) are substrates for the P-glycoprotein (P-gp) efflux pump; 3) have high plasma:brain concentration ratios in the mouse indicative of peripheral restriction; 4) suppress oxidative stress induced EADs in rabbit cardiomyocytes in vitro; and 5) convert oxidative stress induced VT/VF to sinus rhythm in a perfused isolated rat heart preparation. Having met the milestones for the Phase I program positions us to undertake the project described in this Phase II application: lead identification and optimization studies directed toward nomination of two Advanced Candidates for exploratory preclinical safety studies. The proposed work will further leverage our predictive modeling capabilities and focus on designing compounds that in addition to being potent for binding to the ?2? subunit have favorable pharmacokinetic properties including the combination of oral bioavailability and peripheral restriction; clean off-target profiles including limited interaction with safety-relevant cardiac ion channels; demonstrated anti-arrhythmic efficacy in the rabbit cardiomyocyte and isolated rat heart models of our collaborators at the UCLA CVRL; and demonstrated favorable effects on EADs and VT/VF without negative impact on contractility in an innovative iPSC-derived cardiomyocyte-based, matured human cardiac tissue model (Biowire? II) developed by TARA Biosystems.